This application is a 371 of PCT/JP00/00560 filed Feb. 2, 2000.
The present invention relates to a novel benzamide derivative or a salt thereof which has an excellent enhancing effect on gastrointestinal tract motility and is useful as an agent for therapeutic treatment of digestive diseases, in particular, an agent for improving function of gastrointestinal tract motility.
Japanese Patent Unexamined Publication (Kokai) No. 5-262724/1993 filed by the present applicant discloses that 4-(4-amino-5-chloro-2-methoxybenzamido)-1-piperidineacetic acid and ethyl ester derivative thereof have enhancing actions on gastrointestinal tract functions (enhancing action on upper gastrointestinal tract motility and also enhancing action on lower gastrointestinal tract motility).
The aforementioned known compounds have been revealed to have enhancing actions on motility of upper gastrointestinal tract and lower gastrointestinal tract. However, 4-(4-amino-5-chloro-2-methoxybenzamido)-1-piperidineacetic acid has a problem of insufficient oral absorbability. Ethyl ester derivative thereof also has a problem from viewpoints of efficacy and safety, e.g., the derivative is not suitable for oral administration because it causes undesirable side effects such as vomiting. Accordingly, it has been desired to develop a medicament which has improved oral absorbability compared to 4-(4-amino-5-chloro-2-methoxybenzamido)-1-piperidine-acetic acid, and has reduced or no side effect such as those caused by the ethyl ester derivative thereof.
The inventors of the present invention conducted keen researches on the behavior of acetic acid esters of the aforementioned known benzamide derivative to solve the aforementioned problems. As a result, they found that novel benzamide derivatives of the present invention, i.e., ester derivatives of an alkyl having 3 to 6 carbon atoms that has a larger number of carbon atoms than that of the known benzamide derivative, had unexpectedly high enhancing effects on gastrointestinal tract motility. They also found that the emetic action caused by the ethyl ester derivative was reduced or eliminated in these compounds, and the compounds were extremely useful as an agent for therapeutic treatment of digestive diseases that can be administered orally, in particular, an agent for improving function of gastrointestinal tract motility such as a defecation stimulating agent. The present invention was achieved on the basis of these findings.
The present invention thus relates to novel compounds represented by the following general formula (I) or salts thereof: 
wherein R represents an alkyl group having 3 to 6 carbon atoms, preferably represents a straight or branched chain alkyl group having 3 to 6 carbon atoms.
According to preferred embodiments of the present invention, there are provided compounds represented by the aforementioned general formula (I) wherein R represents an alkyl group having 4 to 5 carbon atoms, preferably a straight or branched chain alkyl group having 4 to 5 carbon atoms. For example, those having n-butyl group or n-pentyl group as R are provided.
From another aspect of the present invention, there are provided medicaments comprising a compound represented by the aforementioned general formula (I) or a physiologically acceptable salt thereof as an active ingredient. The medicaments provided by the present invention are suitably used as, for example, a medicament for therapeutic and/or preventive treatment of digestive diseases, in particular, as a medicament for improving function of gastrointestinal tract motility.
From further aspect of the present invention, there are provided a use of a compound represented by the aforementioned general formula (I) or a physiologically acceptable salt thereof for the manufacture of the aforementioned medicaments; a method for therapeutic and/or preventive treatment of a digestive disease which comprises the step of administering to a mammal including a human a therapeutically and/or preventively effective amount of a compound represented by the aforementioned general formula (I) or a physiologically acceptable salt thereof; and a method for improving function of gastrointestinal tract motility which comprises the step of administering to a mammal including a human a therapeutically and/or preventively effective amount of a compound represented by the aforementioned general formula (I) or a physiologically acceptable salt thereof.
In the aforementioned general formula (I) according to the present invention, the alkyl group having 3 to 6 carbon atoms represented by R may be straight, branched, cyclic, or a combination thereof, and preferably a straight or branched chain alkyl group. Examples of the alkyl group having 3 to 6 carbon atoms include, for example, n-propyl group, isopropyl group, cyclopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, cyclobutyl group, cyclopropylmethyl group, n-pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-cyclopropylethyl group, 2-cyclopropylethyl group, 2-methylcyclopropylmethyl group, cyclobutylmethyl group, n-hexyl group, isohexyl group, cyclopentylmethyl group and the like. Examples of the straight or branched chain alkyl group include, for example, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, tert-pentyl group, n-hexyl group, isohexyl group and the like.
The compounds represented by the aforementioned general formula (I) according to the present invention may be converted into salts, preferably physiologically acceptable salts, as required. The produced salts may further be converted into free base compounds. Examples of the salts of the compounds according to the present invention include acid addition salts. Examples include salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, salts with organic acids such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, pivalic acid, trifluoroacetic acid, acrylic acid, oleic acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, malonic acid, lactic acid, glutaric acid, sebacic acid, gluconic acid, lauric acid, stearic acid, undecanoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, benzoic acid, phthalic acid, cinnamic acid, p-toluenesulfonic acid, nicotinic acid, picric acid, adipic acid, aspartic acid, glutamic acid, 10-camphorsulfonic acid, optically active substances thereof and the like.
The compounds represented by the aforementioned general formula (I) or salts thereof according to the present invention may exist as any crystal forms depending on manufacturing conditions, and they may also exist any hydrates or solvates. The crystal forms, hydrates, solvates, and mixtures thereof also fall within the scope of the present invention. In addition, the compounds represented by the aforementioned general formula (I) according to the present invention may have one or more asymmetric carbon atoms depending on type of R. Any optically active compounds or diastereomers based on one or more asymmetric carbon atoms, any mixtures thereof or racemates fall within the scope of the present invention.
Specific examples of the compounds represented by the aforementioned general formula (I) according to the present invention include the following compounds and salts thereof. However, the present invention is not limited to these examples.
(1) n-Propyl 4-(4-amino-5-chloro-2-methoxybenzamido)-1-piperidineacetate
(2) Isopropyl 4-(4-amino-5-chloro-2-methoxybenzamido)-1-piperidineacetate
(3) n-Butyl 4-(4-amino-5-chloro-2-methoxybenzamido)-1-piperidineacetate
(4) Isobutyl 4-(4-amino-5-chloro-2-methoxybenzamido)-1-piperidineacetate
(5) n-Pentyl 4-(4-amino-5-chloro-2-methoxybenzamido)-1-piperidineacetate
(6) Isopentyl 4-(4-amino-5-chloro-2-methoxybenzamido)-1-piperidineacetate
(7) n-Hexyl 4-(4-amino-5-chloro-2-methoxybenzamido)-1-piperidineacetate
(8) Isohexyl 4-(4-amino-5-chloro-2-methoxybenzamido)-1-piperidineacetate
Preferred compounds of the present invention include the following compounds.
(1) n-Butyl 4-(4-amino-5-chloro-2-methoxybenzamido)-1-piperidineacetate
(2) n-Pentyl 4-(4-amino-5-chloro-2-methoxybenzamido)-1-piperidineacetate
The compounds represented by the aforementioned general formula (I) of the present invention can be prepared, for example, by the methods explained below. However, the methods for preparing the compounds are not limited to these methods.
According to the first embodiment of preparation of the compounds of the present invention, a compound represented by the aforementioned general formula (I) can be prepared by allowing an amine compound represented by the following formula (II): 
to react in a solvent in the presence of a base with a compound represented by the following general formula (III):
Xxe2x80x94CH2COORxe2x80x83xe2x80x83(III)
wherein R has the same meaning as that defined above, and X represents a halogen atom or a leaving group such as p-toluenesulfonyloxy group and methanesulfonyloxy group.
The solvents used in the preparation may be any solvents so long as they does not inhibit the reaction. Examples include alcoholic solvents such as methanol, ethanol, isopropanol, tert-butanol, and 2-methoxyethanol, aromatic hydrocarbonic solvents such as benzene, toluene, and xylene, aprotic polar solvents such as ethyl acetate, acetone, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide and the like. Examples of the base used include, for example, inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate and the like. The reaction may be performed within a temperature range of from room temperature to a refluxing temperature of a solvent.
According to the second embodiment of preparation of the compounds of the present invention, a compound represented by the aforementioned general formula (I) can be prepared by allowing a carboxylic acid compound represented by the following formula (IV): 
to react with a carboxylic acid activator in a conventional manner to convert the carboxylic acid into an acid chloride, mixed acid anhydride or the like, and then allowing the resulting product to react in a solvent in the presence or absence of a base with an amine compound represented by the following general formula (V): 
wherein R has the same meaning as that defined above.
Examples of the carboxylic acid activator used in the above preparation include, for example, thionyl chloride, oxalyl chloride, ethyl chloroformate, pivaloyl chloride, 1,1xe2x80x2-carbonyldiimidazole, 1,3-dicyclohexylcarbodiimide, propylphosphonic acid anhydride and the like. The solvents used may be any solvents so long as they does not inhibit the reaction. Examples include halogenated hydrocarbonic solvents such as methylene chloride, chloroform, and 1,2-dichloroethane, aromatic hydrocarbonic solvents such as benzene, toluene, and xylene, aprotic polar solvents such as ethyl acetate, acetone, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide and the like. Example of the base used include, for example, organic bases such as triethylamine, N,N-diisopropyl-ethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene, pyridine, and 4-dimethylamino-pyridine, inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate and the like. The reaction may be performed within a temperature range of from 0xc2x0 C. to a refluxing temperature of a solvent.
According to the third embodiment of preparation of the compounds of the present invention, a compound represented by the aforementioned general formula (I) can be prepared by allowing a carboxylic acid compound represented by the following formula (VI): 
to react in a solvent in the presence of a base with a compound represented by the following general formula (VII):
Yxe2x80x94Rxe2x80x83xe2x80x83(VII)
wherein R has the same meaning as that defined above, and Y represents a halogen atom or a leaving group such as p-toluenesulfonyloxy group and methanesulfonyloxy group.
The solvents used in the preparation may be any solvents so long as they do not inhibit the reaction. Examples include aprotic polar solvents such as ethyl acetate, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, and dimethyl sulfoxide and the like. Example of the base used include, for example, inorganic bases such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate, and organic bases such as triethylamine, N,N-diisopropylethylamine, sodium methoxide, sodium ethoxide, 1,8-diazabicyclo[5.4.0]-7-undecene and the like. The reaction may be performed within a temperature range of from 0xc2x0 C. to a refluxing temperature of a solvent.
According to the fourth embodiment of preparation of the compounds of the present invention, a compound represented by the aforementioned general formula (I) can be prepared by allowing a carboxylic acid compound represented by the aforementioned formula (VI) to react in the presence of an acid catalyst with an alcohol compound represented by the following general formula (VIII):
HOxe2x80x94Rxe2x80x83xe2x80x83(VIII)
wherein R has the same meaning as that defined above.
Examples of the acid catalyst used in the preparation include, for example, hydrogen chloride, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid and the like. The alcohol compound represented by the aforementioned general formula (VIII) is used in a large excess amount so that it can also serve as a reaction solvent. The reaction is performed within a temperature range of from room temperature to a refluxing temperature of a solvent.
The starting materials used for the preparation of the compounds of the present invention are known compounds with a few exceptions. As for novel compounds, their preparations are described as Reference Examples.
The medicaments comprising as an active ingredient the compound represented by the aforementioned general formula (I) or a physiologically acceptable salt thereof according to the present invention are generally administered as preparations for oral administration such as capsules, tablets, subtilized granules, granules, powders and syrups, or preparations for parenteral administration such as suppositories. These preparations can be manufactured in a conventional manner by adding one or more of pharmacologically or pharmaceutically acceptable additives to the compound represented by the aforementioned general formula (I) or a physiologically acceptable salt thereof according to the present invention. As the pharmacologically or pharmaceutically acceptable additives used for preparations for oral administration or suppositories, additives for pharmaceutical preparations such as, for example, excipients such as lactose, D-mannitol, sucrose, corn starch, and crystalline cellulose; disintegrators such as carboxymethylcellulose, calcium carboxymethylcellulose, partly pregelatinized starch, croscarmellose sodium, and crospovidone; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone; lubricants such as magnesium stearate, talc, hydrogenated oil, dimethylpolysiloxane, hydrated silicon dioxide, colloidal silicon dioxide, and carnauba wax; plasticizers such as triethyl citrate, fatty acid glycerin esters, and polyethylene glycol; coating agents such as hydroxypropylmethylcellulose, sucrose, and titanium oxide; bases such as polyethylene glycol, and hard fat and the like may be used.
Doses of the medicament of the present invention may vary depending on symptoms or the age of a patient and the like. Generally, a dose for an adult in an amount of 0.1 to 500 mg for oral administration, or 0.01 to 300 mg for parenteral administration may be administered once or several times as divided portions in a day.